DESCRIPTION (Investigator's Abstract): This is a request for the continuation of a research program that has been concerned with the involvement of fibrous proteins in Alzheimer's disease patients. The new work proposed now focuses exclusively on the role of a single protein and its derivatives (the amyloid beta protein precursor) in the genesis of the progressive, neuritic and glial changes that invariably accompany Alzheimer's disease. A hypothesis implicating amyloid beta protein precursor in the initiation of a complex cascade of molecular and cellular changes that eventually produce the dementia of Alzheimer's disease is presented. This hypothesis is introduced because the presence of the amyloid beta protein seems linked to aging and alzheimer's disease having a wide spread existence inside and outside brain in Alzheimer's disease and because several laboratories have reported that amorphous, largely non-filamentous, deposits of amyloid beta protein appear to precede neuronal or glial cytopathology in Alzheimer's disease and Down's Syndrome. The new aims are 1) to define the DNA sequences, protein modifications and proteolytic processing of APP in many different species, species that invariably develop amyloid beta protein deposited in tissues outside of the brain, especially the skin, 3) to assess the biological effects of amyloid beta protein 1-40 on primary neurons, astrocytes and microglial in vitro; 4) to determine the exact site of normal constitutive cleavage of APP in vivo using human CSF and urine; and 5) to search for an endothelial cell receptor that could bind and take up the circulating forms of APP that have recently been identified in blood by these investigators.